Current therapies for OA simply alleviate symptoms of advanced disease rather than inhibit the processes that drive the disease. A better understanding of the mechanisms underlying the pathogenesis of OA would undoubtedly yield new therapeutic approaches. Although OA was long considered a purely mechanical disorder, it is becoming clear that it also involves inflammation and activation of immune cells. Synovial tissues of individuals with OA contain inflammatory cytokines and are infiltrated with both innate and adaptive immune cells, and the presence of synovial inflammation predicts more rapid cartilage destruction. These infiltrating immune cells express Fc receptors (FcRs), which normally serve to protect against infection by binding to antibodies and thereby triggering the release of inflammatory and cytotoxic mediators. However, aberrant activation or regulation of FcR-mediated signaling can lead to inflammatory and autoimmune diseases. We have garnered evidence that FcRs also play a central role in the pathogenesis of OA. We found that mice lacking the common ?-chain, through which several of the activating FcRs signal, are resistant to cartilage degeneration in a mouse model of OA. Mice deficient specifically in Fc?RIII, which does not signal through the -chain but has been shown to mediate autoantibody-induced tissue damage and inflammation, were also resistant. We hypothesize that one or more activating FcR contributes to the pathogenesis of OA by inducing FcR-expressing immune cells in OA synovial tissue to release inflammatory, vasoactive, cytotoxic, and degradative molecules that in turn contribute to the synovitis, cell death, and cartilage erosion characteristic of OA. Antigen-bound antibodies activate FcRs, and antibodies directed against joint components are present in OA synovial fluid, synovial tissue, and cartilage. Findings in mice indicate that antibodies to various joint components can elicit inflammatory joint destruction. It is possible that such antibodies develop following exposure of cartilage components to the immune system- owing to mechanical cartilage breakdown-and contribute to inflammatory joint destruction in OA by activating FcRs. We propose to use genetically deficient mice, an established mouse model of OA, and samples from patients with OA to (i) determine whether activating FcRs promote mouse OA, and whether they do so by activating mast cells, macrophages, or other immune cells; (ii) determine how early in the development of human OA FcR-expressing immune cells infiltrate the synovial joints; (iii) determine whether levels of FcR expression or levels of immune-cell activation correlate with levels of OA-associated inflammation or with disease severity in human OA; and (iv) determine whether debris from human OA cartilage can activate innate immune cells in an FcR-dependent manner. Several approaches to targeting FcRs are being developed for the treatment of inflammatory disorders. Targeting FcRs, which could prevent the triggering of a cascade of different inflammatory mediators, may prove more therapeutically efficacious than targeting a single inflammatory mediator (the latter being an approach that has so far proven unsuccessful in OA). Thus, by shedding light on the role of FcRs in OA, success of the proposed studies could open up new avenues for the treatment of OA, for which disease- modifying treatments are urgently needed.